WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 200100
CAS#: 497839-62-0
Description: AEE-788 is an orally bioavailable multiple-receptor tyrosine kinase inhibitor. AEE788 inhibits phosphorylation of the tyrosine kinases of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and vascular endothelial growth factor receptor 2 (VEGF2), resulting in receptor inhibition, the inhibition of cellular proliferation, and induction of tumor cell and tumor-associated endothelial cell apoptosis. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).
MedKoo Cat#: 200100
Name: AEE-788
CAS#: 497839-62-0
Chemical Formula: C27H32N6
Exact Mass: 440.26885
Molecular Weight: 440.58
Elemental Analysis: C, 73.60; H, 7.32; N, 19.07
Synonym: AEE788; AEE 788; AEE-788.
IUPAC/Chemical Name: (R)-6-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-N-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine.
InChi Key: OONFNUWBHFSNBT-HXUWFJFHSA-N
InChi Code: InChI=1S/C27H32N6/c1-3-32-13-15-33(16-14-32)18-21-9-11-23(12-10-21)25-17-24-26(28-19-29-27(24)31-25)30-20(2)22-7-5-4-6-8-22/h4-12,17,19-20H,3,13-16,18H2,1-2H3,(H2,28,29,30,31)/t20-/m1/s1
SMILES Code: C[C@@H](NC1=C2C(NC(C3=CC=C(CN4CCN(CC)CC4)C=C3)=C2)=NC=N1)C5=CC=CC=C5
Appearance: Solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
| Biological target: | AEE788 is an inhibitor of the EGFR and ErbB2 with IC50 values of 2 and 6 nM, respectively. |
| In vitro activity: | This study analyzed the ability of AEE788 to induce apoptosis using Annexin-V and propidium iodide by flow cytometric analysis. THP-1, MOLM-13, and MV4-11 cell lines were treated in vitro with different concentrations of AEE788 for 48 hours. AEE788 induced apoptosis of the AML cells in a dose-dependent manner (Fig. 1A). An apoptosis response of 50% was induced at a concentration of 10 μM for MOLM-13 and MV4-11, and of 15 μM for THP-1 cells. Reference: Exp Hematol. 2010 Aug;38(8):641-52. https://pubmed.ncbi.nlm.nih.gov/20380868/ |
| In vivo activity: | This study compared the antitumor activity of AEE788 against Daoy, DaoyPt, DaoyHER2, and DaoyV xenografts. AEE788 caused a statistically significant reduction in tumor volume of Daoy and DaoyPt xenografts, with a TVI of 51% and 45%, respectively (Figure 4, A and B). DaoyV xenografts behaved as Daoy (data not shown). On the DaoyHER2 xenografts, AEE788 induced a more pronounced tumor inhibition (TVI = 72%; Figure 4C). All the mice survived until the end of the 4-week treatment period, with a less than 15% body weight loss at worst, which was partially recovered by the end of the experiment (Figure 4, D–F). Reference: Transl Oncol. 2010 Oct; 3(5): 326–335. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935636/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 51.77 | 117.5 | |
| DMSO:PBS (pH 7.2) (1:3) | 0.25 | 0.57 | |
| DMF | 25.0 | 56.74 | |
| Ethanol | 5.0 | 11.35 |
The following data is based on the product molecular weight 440.58 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
| Formulation protocol: | 1. Barbarroja N, Torres LA, Rodriguez-Ariza A, Valverde-Estepa A, Lopez-Sanchez LM, Ruiz-Limon P, Perez-Sanchez C, Carretero RM, Velasco F, López-Pedrera C. AEE788 is a vascular endothelial growth factor receptor tyrosine kinase inhibitor with antiproliferative and proapoptotic effects in acute myeloid leukemia. Exp Hematol. 2010 Aug;38(8):641-52. doi: 10.1016/j.exphem.2010.03.017. Epub 2010 Apr 7. PMID: 20380868. 2. Venkatesan P, Das S, Krishnan MM, Chakraborty C, Chaudhury K, Mandal M. Effect of AEE788 and/or Celecoxib on colon cancer cell morphology using advanced microscopic techniques. Micron. 2010 Apr;41(3):247-56. doi: 10.1016/j.micron.2009.10.008. Epub 2009 Nov 10. PMID: 19945288. 3. Meco D, Servidei T, Zannoni GF, Martinelli E, Prisco MG, de Waure C, Riccardi R. Dual Inhibitor AEE788 Reduces Tumor Growth in Preclinical Models of Medulloblastoma. Transl Oncol. 2010 Oct 1;3(5):326-35. doi: 10.1593/tlo.10163. PMID: 20885895; PMCID: PMC2935636. 4. Deng M, Huang H, Jin H, Dirsch O, Dahmen U. The anti-proliferative side effects of AEE788, a tyrosine kinase inhibitor blocking both EGF- and VEGF-receptor, are liver-size-dependent after partial hepatectomy in rats. Invest New Drugs. 2011 Aug;29(4):593-606. doi: 10.1007/s10637-010-9394-6. Epub 2010 Feb 12. PMID: 20148349. |
| In vitro protocol: | 1. Barbarroja N, Torres LA, Rodriguez-Ariza A, Valverde-Estepa A, Lopez-Sanchez LM, Ruiz-Limon P, Perez-Sanchez C, Carretero RM, Velasco F, López-Pedrera C. AEE788 is a vascular endothelial growth factor receptor tyrosine kinase inhibitor with antiproliferative and proapoptotic effects in acute myeloid leukemia. Exp Hematol. 2010 Aug;38(8):641-52. doi: 10.1016/j.exphem.2010.03.017. Epub 2010 Apr 7. PMID: 20380868. 2. Venkatesan P, Das S, Krishnan MM, Chakraborty C, Chaudhury K, Mandal M. Effect of AEE788 and/or Celecoxib on colon cancer cell morphology using advanced microscopic techniques. Micron. 2010 Apr;41(3):247-56. doi: 10.1016/j.micron.2009.10.008. Epub 2009 Nov 10. PMID: 19945288. |
| In vivo protocol: | 1. Meco D, Servidei T, Zannoni GF, Martinelli E, Prisco MG, de Waure C, Riccardi R. Dual Inhibitor AEE788 Reduces Tumor Growth in Preclinical Models of Medulloblastoma. Transl Oncol. 2010 Oct 1;3(5):326-35. doi: 10.1593/tlo.10163. PMID: 20885895; PMCID: PMC2935636. 2. Deng M, Huang H, Jin H, Dirsch O, Dahmen U. The anti-proliferative side effects of AEE788, a tyrosine kinase inhibitor blocking both EGF- and VEGF-receptor, are liver-size-dependent after partial hepatectomy in rats. Invest New Drugs. 2011 Aug;29(4):593-606. doi: 10.1007/s10637-010-9394-6. Epub 2010 Feb 12. PMID: 20148349. |
1: Hoffmann S, Burchert A, Wunderlich A, Wang Y, Lingelbach S, Hofbauer LC, Rothmund M, Zielke A. Differential effects of cetuximab and AEE 788 on epidermal growth factor receptor (EGF-R) and vascular endothelial growth factor receptor (VEGF-R) in thyroid cancer cell lines. Endocrine. 2007 Apr;31(2):105-13. doi: 10.1007/s12020-007-0008-9. PMID: 17873319.
2: Yun CH, Boggon TJ, Li Y, Woo MS, Greulich H, Meyerson M, Eck MJ. Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. Cancer Cell. 2007 Mar;11(3):217-27. doi: 10.1016/j.ccr.2006.12.017. PMID: 17349580; PMCID: PMC1939942.
3: Adjei AA. Targeting multiple signal transduction pathways in lung cancer. Clin Lung Cancer. 2005 Sep;7 Suppl 1:S39-44. doi: 10.3816/clc.2005.s.006. PMID: 16159418.
4: Bayés M, Rabasseda X, Prous JR. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2005 Jun;27(5):331-72. PMID: 16082422.
5: Toffoli G, De Mattia E, Cecchin E, Biason P, Masier S, Corona G. Pharmacology of epidermal growth factor inhibitors. Int J Biol Markers. 2007 Jan-Mar;22(1 Suppl 4):S24-39. PMID: 17520578.
6: Finn RS, Zhu AX. Targeting angiogenesis in hepatocellular carcinoma: focus on VEGF and bevacizumab. Expert Rev Anticancer Ther. 2009 Apr;9(4):503-9. doi: 10.1586/era.09.6. PMID: 19374603.
7: Sartore-Bianchi A, Ricotta R, Cerea G, Maugeri MR, Siena S. Rationale and clinical results of multi-target treatments in oncology. Int J Biol Markers. 2007 Jan-Mar;22(1 Suppl 4):S77-87. PMID: 17520585.
8: Niculescu-Duvaz D, Whittaker S, Springer C, Marais R. The EGF receptor Hokey- Cokey. Cancer Cell. 2007 Mar;11(3):209-11. doi: 10.1016/j.ccr.2007.02.021. PMID: 17349577.
9: Burzynski SR. Treatments for astrocytic tumors in children: current and emerging strategies. Paediatr Drugs. 2006;8(3):167-78. doi: 10.2165/00148581-200608030-00003. PMID: 16774296.
10: Barlesi F, Breen D. Thérapeutiques ciblant la voie des HER dans les cancers ORL et thoraciques [Targeting HER pathway in head and neck and thoracic cancers]. Bull Cancer. 2009;96 Suppl 1:S35-43. French. doi: 10.1684/bdc.2008.0774. PMID: 19433372.
11: Meng X, Li Y, Tang H, Mao W, Yang H, Wang X, Ding X, Xie S. Drug response to HER2 gatekeeper T798M mutation in HER2-positive breast cancer. Amino Acids. 2016 Feb;48(2):487-97. doi: 10.1007/s00726-015-2102-2. Epub 2015 Oct 6. PMID: 26439378.
12: Schaffrath J, Schmoll HJ, Voigt W, Müller LP, Müller-Tidow C, Mueller T. Efficacy of targeted drugs in germ cell cancer cell lines with differential cisplatin sensitivity. PLoS One. 2017 Jun 7;12(6):e0178930. doi: 10.1371/journal.pone.0178930. PMID: 28591197; PMCID: PMC5462387.
13: Birkeland AC, Yanik M, Tillman BN, Scott MV, Foltin SK, Mann JE, Michmerhuizen NL, Ludwig ML, Sandelski MM, Komarck CM, Carey TE, Prince ME, Bradford CR, McHugh JB, Spector ME, Brenner JC. Identification of Targetable ERBB2 Aberrations in Head and Neck Squamous Cell Carcinoma. JAMA Otolaryngol Head Neck Surg. 2016 Jun 1;142(6):559-67. doi: 10.1001/jamaoto.2016.0335. PMID: 27077364; PMCID: PMC4911238.
14: Sullenberger C, Piqué D, Ogata Y, Mensa-Wilmot K. AEE788 Inhibits Basal Body Assembly and Blocks DNA Replication in the African Trypanosome. Mol Pharmacol. 2017 May;91(5):482-498. doi: 10.1124/mol.116.106906. Epub 2017 Feb 28. PMID: 28246189; PMCID: PMC5399642.
15: Valverde A, Peñarando J, Cañas A, López-Sánchez LM, Conde F, Hernández V, Peralbo E, López-Pedrera C, de la Haba-Rodríguez J, Aranda E, Rodríguez-Ariza A. Simultaneous inhibition of EGFR/VEGFR and cyclooxygenase-2 targets stemness- related pathways in colorectal cancer cells. PLoS One. 2015 Jun 24;10(6):e0131363. doi: 10.1371/journal.pone.0131363. PMID: 26107817; PMCID: PMC4479446.
16: Rappl A, Piontek G, Schlegel J. EGFR-dependent migration of glial cells is mediated by reorganisation of N-cadherin. J Cell Sci. 2008 Dec 15;121(Pt 24):4089-97. doi: 10.1242/jcs.027995. Epub 2008 Nov 25. PMID: 19033391.
17: Venkatesan P, Bhutia SK, Singh AK, Das SK, Dash R, Chaudhury K, Sarkar D, Fisher PB, Mandal M. AEE788 potentiates celecoxib-induced growth inhibition and apoptosis in human colon cancer cells. Life Sci. 2012 Oct 22;91(15-16):789-99. doi: 10.1016/j.lfs.2012.08.024. Epub 2012 Aug 24. PMID: 22922496.
18: Weihua Z, Tsan R, Schroit AJ, Fidler IJ. Apoptotic cells initiate endothelial cell sprouting via electrostatic signaling. Cancer Res. 2005 Dec 15;65(24):11529-35. doi: 10.1158/0008-5472.CAN-05-2718. PMID: 16357162; PMCID: PMC1404497.
19: Reardon DA, Cloughesy T, Rich J, Alfred Yung WK, Yung L, DiLea C, Huang J, Dugan M, Mietlowski W, Maes A, Conrad C. Pharmacokinetic drug interaction between AEE788 and RAD001 causing thrombocytopenia in patients with glioblastoma. Cancer Chemother Pharmacol. 2012 Jan;69(1):281-7. doi: 10.1007/s00280-011-1754-1. Epub 2011 Oct 9. PMID: 21984222.
20: Zhao H, Tang C, Cui K, Ang BT, Wong ST. A screening platform for glioma growth and invasion using bioluminescence imaging. Laboratory investigation. J Neurosurg. 2009 Aug;111(2):238-46. doi: 10.3171/2008.8.JNS08644. PMID: 19199503.
AEE788 is a multitargeted human epidermal receptor (HER) 1/2 and vascular endothelial growth factor receptor (VEGFR) 1/2 receptor family tyrosine kinases inhibitor with IC50 of 2, 6, 77, 59 nM for EGFR, ErbB2, KDR, and Flt-1. In cells, growth factor-induced EGFR and ErbB2 phosphorylation was also efficiently inhibited with IC50s of 11 and 220 nM, respectively. It efficiently inhibited growth factor-induced EGFR and ErbB2 phosphorylation in tumors for >72 h, a phenomenon correlating with the antitumor efficacy of intermittent treatment schedules. It also inhibits VEGF-induced angiogenesis in a murine implant model. It has potential as an anticancer agent targeting deregulated tumor cell proliferation as well as angiogenic parameters. (http://en.wikipedia.org/wiki/AEE788)
AEE788 is a multitargeted human epidermal receptor (HER) 1/2 and vascular endothelial growth factor receptor (VEGFR) 1/2 receptor family tyrosine kinases inhibitor with IC50 of 2, 6, 77, 59 nM for EGFR, ErbB2, KDR, and Flt-1. In cells, growth factor-induced EGFR and ErbB2 phosphorylation was also efficiently inhibited with IC50s of 11 and 220 nM, respectively. It efficiently inhibited growth factor-induced EGFR and ErbB2 phosphorylation in tumors for >72 h, a phenomenon correlating with the antitumor efficacy of intermittent treatment schedules. It also inhibits VEGF-induced angiogenesis in a murine implant model. It has potential as an anticancer agent targeting deregulated tumor cell proliferation as well as angiogenic parameters. (http://en.wikipedia.org/wiki/AEE788)
